Topical clonidine preparation

ABSTRACT

An aqueous gel in unit dose form and suitable for topical delivery of clonidine and comprising clonidine, a water-gelling amount of a pharmaceutically acceptable gelling agent and having a pH value in the range of about 6 to about 8.5. Clonidine is present in an amount in the range of about 0.05 to about 3.5 milligrams per unit dose and at a concentration in the range of about 0.01 to about 0.5 weight percent.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 09/427,367, filedOct. 26, 1999, now U.S. Pat. No. 6,147,102.

TECHNICAL FIELD OF THE INVENTION

This invention relates to the relief of sympathetically maintainedperipheral neuropathic pain syndromes, and in particular, to the use ofgel compositions containing clonidine.

BACKGROUND OF THE INVENTION

Sympathetically maintained peripheral neuropathic pain syndromes ofacute or chronic origin can encompass painful diabetic neuropathy (PDN),post-herpetic neuralgia (PHN), complex regional pain syndrome(CRPS) andlike chronic non-malignant neuropathic pain syndromes. Patients withsympathetically maintained peripheral neuropathic pain syndromestypically have stimulus-independent (ongoing) pain andstimulus-dependent pain (hyperalgesia).

Conventional treatments for these pain syndromes include oraladministration of tricyclic antidepressants, anti-epileptics, and othermiscellaneous neurological agents. Some prior attempts also have beenmade to treat sympathetically maintained peripheral neuropathic painsyndromes with adrenergic compounds such as clonidine or phentolamine.

Clonidine, in particular, is a potent α₂-adrenergic partial agonist usedprimarily for the treatment of hypertension (Jarrott et al., “Clonidine:Understanding its disposition, sites, and mechanism of action”, Clin.Exp. Pharm. Physiol., 14, 471-479 (1987)). This drug stimulatesα₂-adrenoceptors in the vasomotor centers, causing a reduction ofsympathetic outflow from the central nervous system. Both cardiac outputand peripheral resistance are reduced resulting in a decrease in bloodpressure. Higher concentrations cause a vasoconstriction by activationof postsynaptic receptors in vascular smooth muscle. However, thesignificant advantages of the drug are counter balanced by certaintroublesome side effects including dryness of the mouth and adiscouraging dizziness. Therefore, the blood concentration of clonidinemust be controlled within a narrow therapeutic window.

Clonidine and related α₂-adrenergic agonists have been reported tomodify nociception in animal models. See Yaksh, T. L., “Pharmacology of,spinal adrenergic systems which modulate spinal nociceptive processing”,Pharmacol. Biochem. Behav., 22, 845-858 (1985); and Nakamura et al.,“Peripheral analgesic action of clonidine: mediation by release ofendogenous enkephalin-like substances”, Eur. J. Pharmacol., 146, 223-228(1988). In clinical studies, single doses of epidural clonidine havebeen reported to relieve post-operative pain (Mendez et al., “Epiduralclonidine analgesia after cesarean section”, Anesthesiology, 73, 848-852(1990)), cancer pain (Eisenach et al., “Epidural clonidine analgesia forintractable cancer pain:phase I”, Anesthesiology, 71, 647-552 (1989)),and pain due to arachnoiditis (Glynn et al., “A double-blind comparisonbetween epidural morphine and epidural clonidine in patients withchronic non-cancer pain”, Pain, 34, 123-128 (1988)).

In a controlled trial of single oral doses of 0.2 milligrams (mg)clonidine in 40 patients with postherpetic neuralgia, observed painrelief was greater than that produced by doses of placebo or 120 mgcodeine, but the modest analgesia was accompanied by troublesome levelsof sedation and dizziness at the time of peak clonidine levels. (Max etal., “Association of pain relief with drug side effects in postherpeticneuralgia: a single-dose study of clonidine, codeine, ibuprofen andplacebo”, Clin. Pharmacol. Ther., 43, 363-371 (1988)).

Some attempts have been made to relieve pain, allodynia and hyperalgesiaemploying transdermal patches containing clonidine, but the effectsachieved were restricted to the skin underlying the patch. Hyperalgesiais defined as a leftward shift of the stimulus-response function, suchthat a lowering of pain threshold or an increase in pain tosuprathreshold stimuli or both is observed. The decrease in painthreshold to mechanical or thermal stimuli may be such that lightlystroking the skin evokes pain, a phenomenon sometimes referred to asallodynia.

For example, Davis et al., in “Topical application of clonidine relieveshyperalgesia in patients with sympathetically maintained pain,” Pain,47, 309-318 (1991) reported that delivery of clonidine by transdermalpatch relieved sympathetically maintained hyperalgesia in the skinadjacent to the patch . Likewise, Campbell in U.S. Pat. No. 5,447,947describes hyperalgesia relief with transdermal patches delivering asystemic dose of 0.2 mg and 0.3 mg of clonidine/day (i.e., 30micrograms/square centimeter patch/day), but the zone of relief wasgenerally limited to the skin area at or adjacent the patch site alongwith some skin irritation surrounding the patch site and side effectswere noted.

In a placebo-controlled cross-over pain trial in patients with painfuldiabetic neuropathy utilizing clonidine transdermal patches nostatistically significant differences between treatments were observedby Zeigler et al., “Transdermal clonidine versus placebo in painfuldiabetic neuropathy”, Pain, 48, 403-408 (1992). In a follow-up placebocontrolled pain study in similar patients with painful diabeticneuropathy, transdermal clonidine patches were evaluated using atwo-stage enriched enrollment design by Byas-Smith et al., “Transdermalclonidine compared to placebo in painful diabetic neuropathy using atwo-stage enriched enrollment design”, Pain, 60, 267-274 (1995). Onlytwelve of forty-one patients (29%) who completed the initial course oftreatment were considered clonidine responders. These twelve clonidineresponders were then rechallenged in a second placebo controlled studywhich used the highest dosage available with the transdermal patchsystem. The pain reduction relative to placebo tended to be modestalthough statistically significant (p<0.015).

Based on the foregoing attempts it would appear that relatively higherconcentrations of clonidine are needed at the painful site.Unfortunately, with the dosage forms utilized, higher doses cannot begiven without accompanying undesirable systemic side effects. Whileclonidine is a desirable potent analgesic drug, it has a narrowtherapeutic index.

A desirable treatment for sympathetically maintained peripheralneuropathic pain syndromes, therefore, would be a topical composition ofclonidine that could be spread over the entire painful area to delivertargeted high concentrations to the painful site yet affording minimumsystemic concentrations.

The present gel composition answers the need for deliveringtherapeutically effective amounts of clonidine directly to the affectedregion of patients suffering sympathetically maintained peripheralneuropathic pain syndromes while avoiding undesirable systemic effects.

SUMMARY OF THE INVENTION

Topical aqueous gel compositions containing clonidine are suitable forrelieving sympathetically maintained peripheral neuropathic pain.Sympathetically maintained peripheral neuropathic pain is relieved bytopically applying, to the affected region of a patient suffering fromsuch pain, a pain relieving amount of an aqueous gel comprisingclonidine, and a pharmaceutically acceptable water-gelling agent.

The aqueous gel has a physiologically tolerable pH value. The gelscontain clonidine present in an amount in the range of about 0.01 toabout 0.5 weight percent based on the weight of the gel. A preferred gelcontains clonidine in an amount in the range of about 0.01 to about0.075 weight percent, based on the weight of the gel.

Preferably, the gelling agent is a carbomer, a glycerin polyacrylate, ora mixture thereof. The gelling agent can provide moisturizing,skin-humectant benefits as well. A preservative, a topical anestheticand a supplemental skin-humectant also can be present.

Pain relief was achieved with topically applied amounts of clonidine atdosages preferably in the range of about 2 milligrams per day to about 6milligrams per day.

Advantageously, the topical clonidine gels can be applied and spreadover the entire affected region of a patient suffering from asympathetically maintained peripheral neuropathic pain syndrome, such asfrom diabetic neuropathy, postherpetic neuralgia and like peripheralneuropathic pain syndromes. In addition, these topical clonidine gelsare capable of delivering relatively high amounts of clonidine directlyto the affected region where required while limiting the total amount ofclonidine going into the general circulation to levels that avoid or atleast minimize systemic adverse effects.

BRIEF DESCRIPTION OF THE DRAWING

In the drawing,

FIG. 1 is a graph illustrating clonidine plasma concentrations innanograms/milliliter following regimens of topical applications ofaqueous gels containing 0.1% clonidine applied in unit doses whichprovide total daily dosage amounts of about 3 milligrams and about 6milligrams of clonidine/day in accordance with the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The term “clonidine” as used herein refers toN-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine and includes thepharmaceutically acceptable salts thereof, e.g., the hydrochloride saltthereof.

The term “pharmaceutically acceptable” as used herein means that theingredient is not a known irritant or sensitizer of human skin and hasnot been prohibited or restricted from use in topical skin products bythe Food and Drug Administration.

The term “gel” as used herein refers to viscous, aqueous compositionspreferably containing at least about 85 weight percent water on a totalgel weight basis and a sufficient amount of pharmaceutically acceptablewater-gelling agent to produce a viscoelastic composition having athixotropic viscosity.

Topical gels containing clonidine were prepared that provided increasedpain relief for more patients suffering from sympathetically maintainedperipheral neuropathic pain syndromes by delivering clonidine directlyto the entire affected region employing concentrations of clonidinegreater than those of prior art attempts.

The following factors are significant in the development of topical gelformulations of clonidine for treating sympathetically maintainedperipheral neuropathic pain syndromes:

1. The region of pain varies with the condition treated, e.g., painfuldiabetic neuropathy may involve only one foot or both feet, or the feetand hands, or the feet, calves and hands. Therefore, the total dosegiven will vary depending on the region of involvement and thecorresponding amount of gel required to cover the affected regions. Iftoo much clonidine is applied, systemic concentrations of clonidine riseto levels appropriate for antihypertensive therapy and thus causetreatment limiting side effects. The side effects in normotensive peoplecan include dizziness, sedation, drymouth, bradycardia, and hypotension.Therefore, the present formulations and delivery methods balance theamount applied (concentration and total amount) with the size of theregion to be treated with avoidance of high systemic clonidine bloodconcentrations.

2. Another factor is the variability of each individual's perception ofpain and response to treatment. A sufficiently high dose must beavailable to those patients who have higher pain tolerance thresholds.These patients are not likely to respond to allowable systemicconcentrations from oral or patch technology administration.

3. An appropriate gel vehicle is necessary for ease of drugadministration, drug solubility and stability, as well as drugconcentration and pH value to provide the necessary non-ionizedconcentration of drug with the requisite thermodynamic activity foreffective topical delivery and bioavailability.

An effective aqueous topical clonidine gel composition embodying thepresent invention comprises the following constituents:

Ingredient Conc.(% w/w) Clonidine HCl 0.01 to 0.5 Water-gelling agent0.1 to 2 Preservative 0.1 to 2 Topical anaesthetic zero to 5Skin-humectant zero to 5 pH adjusting agent q.s. to final pH 7.5 to 8.5Purified Water USP to 100% q.s.

Clonidine is employed in a therapeutically effective amount, preferablyin the form of clonidine base. The actual concentration of clonidine mayvary, depending on the nature and degree of the pain syndromes beingtreated and whether the drug is being administered for therapeutic orprophylactic purposes. Preferably the total daily amount of clonidineabsorbed by the patient in need of treatment from doses of topicallyapplied gel is not more than about 0.2 nanograms/milliliter, based onblood plasma concentrations to avoid undesirable systemic effects.

The present topical clonidine gel contains at least about 0.01 weightpercent clonidine, based on the total weight of the gel. Preferablyclonidine is present in an amount in the range of about 0.01 to about0.5 weight percent, more preferably in the range of about 0.01 to about0.25 weight percent, and most preferably in the range of about 0.01 toabout 0.075 weight percent, based on the weight of the gel.

Pharmaceutically acceptable water-gelling agents preferably arecarbomers, glyceryl polyacrylates, and combinations thereof. Carbomersare a series of water-gelling homopolymers of acrylic acid crosslinkedwith an allyl ether of pentaerythritol, an allyl ether of sucrose, or anallyl ether of propylene available in various viscosity grades soldunder the trademark designation CARBOPOL® by B.F. Goodrich Company,Cleveland, Ohio. Particularly preferred is CARBOPOL® 980. Glycerylpolyacrylates are esters of glycerine and polyacrylic acid available invarious viscosity grades sold as an aqueous jelly under the trademarkdesignation, HISPAGEL, by Hispano Quimica S. A., Barcelona, Spain. Whena combination of a carbomer and a glyceryl polyacrylate is employed asthe water-gelling agent, the glyceryl polyacrylate preferably is a minorportion of the total amount of water-gelling agent used. Glycerylpolyacrylate, if present, also contributes a skin moisturizing effect.

The water-gelling agent imparts a desirable viscous, thixotropicconsistency to the topical gel when mixed with clonidine and water.Preferably the gel contains at least about 85 percent by weight water,more preferably 95 percent by weight water, based on the total weight ofthe gel. The amount of gelling agent can vary depending on degree of gelviscosity desired. Preferably the amount of water-gelling agent is inthe range of about 0.1 to about 2 weight percent, more preferably ofabout 0.5 to about 1.5 weight percent, and most preferably not more thanabout 1 weight percent, based on the total weight of the gel.

It is known that the skin of patients affected with sympatheticallymaintained peripheral neuropathic pain syndromes, and especiallydiabetic patients affected with diabetic neuropathy, tends to be dry.Conventionally, such patients typically apply skin-moisturizing productsto their skin. In the topical gels of the present invention, thewater-gelling agent may also provide some skin-humectant benefits bymaintaining moisture at the affected site, without interfering with thepain relieving efficacy of the clonidine, thereby minimizing the needfor applying additional skin-moistunzing products.

Optionally, supplemental, water-soluble, skin-humectant adjuvants thathave skin-moisturizing properties or anti-irritant properties also canbe included, so long as they do not interfere with the pain relievingefficacy of the clonidine. Example skin-humectants include but arc notlimited to polyhydric alcohols having two to six carbon atoms permolecule, such as glycerin, sorbitol, propylene glycol, andpolyglycerols having two to ten glycerin units and the like. The amountof skin-humectant, when present, can vary in the range of about 0.1 toabout 5 weight percent, preferably of about 0.5 to about 3 weightpercent, based on the total weight of gel.

Aqueous solutions of carbomer polymers form gels when neutralized with abase. Water-soluble bases which have been used to promote gelling ofcarbomers, such as the CARBOPOL® series of polymers include, forexample, inorganic bases, such as an aqueous solution of NaOH, andorganic bases, such as alkylamines, dialkylamines, trialkylamines,alkanolamines, dialkanolamines, trialkanolamines having one to fourcarbon atoms in the alkyl or alkanol chain and the like. A presentlypreferred inorganic base is NaOH, and a preferred organic base ismonoethanolamine or triethanolamine.

The pharmaceutically effective component of the gel composition,clonidine hydrochloride, is itself acidic in aqueous solution, so somebase neutralization is typically required to promote gelling of thecarbomer. At a pH value of about 8, the topical clonidine gel maycomprise clonidine in both the hydrochloride form and free base form.

Preservatives may be incorporated in an amount effective for inhibitinggrowth of microbes, such as bacteria, yeast and molds, in the gel duringstorage. Any conventional preservative against microbial contaminationof the product can be employed so long as it is pharmaceuticallyacceptable, is unreactive with clonidine, and is non-irritating ornon-sensitizing to human skin. Preferred preservatives are antimicrobialaromatic alcohols, such as benzyl alcohol, phenoxyethanol, phenethylalcohol, and the like, and esters of parahydroxybenzoic acid commonlyreferred to as paraben compounds, such as methyl, ethyl, propyl, andbutyl esters of parahydroxybenzoic acid and the like and mixturesthereof, but are not limited thereto. Particularly preferred are benzylalcohol and phenoxyethanol. The amount of preservative is preferably notmore than about two weight percent, based on the total weight of thegel.

Optionally, a topical, preferably water-soluble, anaesthetic agent, suchas lidocaine and the like, can be included. If present, the amount ofanaesthetic agent can vary in the range of about 0.1 to about 5 weightpercent.

The pH value of the gel can be in a physiologically tolerable range ofabout 4 to about 9, preferably of about 6 to about 8.5, most preferablyof about 7.5 to about 8.25. The term “physiologically tolerable” as usedherein refers to a gel medium that is non-irritating to human skin.

Any suitable method of adjusting the pH value of the aqueous gel may beused. Preferably, sodium hydroxide (NaOH) is added as a concentratedaqueous (10 to 20 weight percent) solution to the aqueous vehiclecontaining the water-gelling agent to bring the final pH value to thedesired level. When carbomer is employed, the gel viscosity typicallyincreases as the carbomer in the gel is neutralized with base, e.g.,with NaOH or triethanolamine, following the recommendations of thecarbomer manufacturer for dissolving and neutralizing the carbomer.

The ingredients listed above may be combined in any order and mannerthat produces a one-phase aqueous gel of the desired consistency and pHvalue with clonidine dissolved therein and substantially evenlydistributed or dispersed throughout.

One preferred method of preparing such a gel involves preparation of anaqueous solution of clonidine with a portion of the water content andthen dissolving the gelling agent therein. The preservative and anyremaining optional ingredients (i.e., topical anaesthetic andskin-humectant adjuvant) can be subsequently included and then the pH ofthe mixture is adjusted by adding the pH adjusting agent as needed tosimultaneously form a gel having the desired viscosity and pH value.

Another method of preparing such gel compositions involves preparationof an aqueous solution of the water-gelling agent, which hereinbelowwill be called “Part A”, by dissolving the gelling agent in a portion ofthe water content according to the manufacturer's directions. Preferablythe gelling agent is dissolved in purified water, such as distilledwater. A separate “Part B” aqueous solution can be prepared comprisingthe clonidine, and, if present, the preservative, topical anaestheticagent, and skin-humectant adjuvant. Parts A and B are then combined, andthe pH of the mixture is adjusted by adding the pH adjusting agent asneeded to simultaneously form a gel having the desired viscosity and pHvalue.

Alternatively, the clonidine, preservative and remaining optionalingredients (i.e., topical anaesthetic and skin-humectant adjuvant) canbe included separately or together in either Part A or Part B.

The gel is preferably packaged in any suitable container indicating useand from which it can be either extruded or dispensed, such as asqueezable tube, syringe, or the like, directly onto the affectedregion. The volume of gel so contained is conveniently and preferablyselected to constitute a predetermined unit dose, such as a single dailydose, or two or more daily doses, or the like, to facilitateadministration of a desired controlled dose to the painful affectedregion of a patient. The package can be initially sealed and be openedat the time of use. If more than a single dose is present, the packageis preferably resealable by a suitable closure means.

A preferred package is a container, such as a bottle and the like,fitted with a pump dispenser that delivers a metered predeterminedstandardized unit dose on actuation.

Another presently preferred package is a moisture-impermeable packetcontaining an intended single unit dose. The packet can be initiallysealed, and be opened at the time of use by tearing, cutting, or thelike at a desired or planned location in the packet after which thepacket is manually squeezed so that the contents are directlyadministratable as desired.

The quantity of clonidine contained in a unit dose ranges from about0.05 milligram (mg) to about 3.5 mg, more preferably in the range ofabout 0.15 to about 0.6 mg, most preferably in the range of about 0.3 toabout 0.5 mg. Such a quantity of unit doses can be administered one tofour times daily, at spaced intervals in a single day and over a periodof days as needed. The total daily dose thus delivered can range fromabout 0.1 to not more than about 6 mg clonidine.

A presently preferred administration procedure is to employ a unit doseof gel to deliver a dose of about 0.3 mg of clonidine administered oneto four times daily to the affected painful region. Those skilled in theart will appreciate that the foregoing dose levels are providedillustratively, and that higher and lower dose levels can be employedwithout departing from the spirit and scope of the present invention.

Desirably, the topical clonidine gel of this invention can be spreadover the entire affected painful region of a patient to deliver targetedhigh concentrations to the painful site yet afford minimum systemicconcentrations. This can be accomplished with the topical gel by varyingthe concentration of clonidine in the gel and by varying the number ofapplications of gel per day to provide therapeutically effective amountswhile minimizing the possibility of systemic effects. The topicalclonidine gel can be applied directly to the affected region preferablyby applying gel and then rubbing the gel into the skin.

Two preliminary studies were conducted to characterize thepharmacokinetics from the application of clonidine gel. In the firststudy a single 2 mg dose of clonidine gel was applied to the skin ofnormotensive volunteers and the clonidine plasma concentrations weremeasured utilizing Gas Chromatograph/Mass Spectrum analysis having alimit of quantitation of 0.025 nanograms/milliliter (ng/ml). With thisdosage, all clonidine plasma concentrations were below the limits ofquantitation. In the second study a 7.5 mg daily dose of clonidine wasapplied. Besides producing measurable plasma concentrations, the dose of7.5 mg clonidine per day produced adverse events, such that thevolunteers prematurely discontinued dosing for intolerable adverseevents after seven days. Following the discontinuation of treatment theclonidine plasma concentrations had a calculated half life of 39-80hours suggesting a prolonged absorption from tissue binding sites intothe blood.

A third pharmacokinetic study described in Example 2 below, wasconducted which compared topical daily doses of 3 mg and 6 mg clonidineand the mean plasma concentrations were found to be not more than about0.2 nanograms/ml as shown in FIG. 1 and no side effects were observed.

It was found that topical applications of clonidine gel have particularanalgesic efficacy in two sympathetically maintained peripheralneuropathic pain syndromes: post-herpetic neuralgia and painful diabeticneuropathy. Pilot trials in patients with these pain syndromes showedthat effective pain relief occurs over a daily dose range of about 2 mgto about 5 mg clondine. Although clonidine doses above five mg per daywere also found to be analgesic, there was no apparent beneficialincrease in analgesia with the higher doses but the frequency andseverity of clonidine related systemic adverse events increased.

It was found that a topical clonidine gel formulation containing 0.05 to0.1 weight percent clonidine applied to the skin of the lowerextremities, such as the foot or leg region from once a day up to threetimes per day affords systemic clonidine plasma concentrations below orat the lower limit of those required for antihypertensive therapy.Advantageously, these topical clonidine gels provide the necessaryamount of on-site clonidine concentration for pain relief and allow thepatient the opportunity to apply needed concentrations to large painregions of the body, e.g., both feet in a diabetic neuropathy patient,feet, calves and hands/fingers in the diabetic patient or large areas ofthe chest or back in postherpetic neuralgia patients.

The following examples further illustrate the present invention and arenot intended to be limited thereto.

EXAMPLE 1

A kilogram (kg) batch of gel was prepared having the following formula:

Gram Components % (w/w) Amount Clonidine Hydrochloride USP 0.05 0.5Benzyl Alcohol NF 1 10 Carbomer¹ 0.5 5 Sodium Hydroxide NF q.s. (10% inwater) to pH 8 Purified Water USP q.s. q.s. to 100% to 1 Kg ¹Carbopol ®980 NF, B.F. Goodrich Corporation

An aqueous solution of clonidine was prepared in about 80% of the totalwater content with stirring agitation employing a propeller-type stirrer(Lightnin mixer) for about five minutes or until homogeneous. Whilemaintaining a stirring vortex, the carbomer was sifted into the vortexof the aqueous clonidine solution and dissolved therein with continuousstirring agitation until a homogenous thin, cloudy liquid dispersion wasobtained. The benzyl alcohol was added to the liquid dispersion andstirring agitation maintained for at least ten minutes.

The pH of the mixture was measured and then adjusted and concurrentlygelled by adding aqueous sodium hydroxide and mixed for about 15-30minutes. For this process step, the dispersion was stirred with a paddlestirrer (Hobart mixer). The pH and water content was adjusted as neededfor the final gel product.

During processing, the pH value may vary in the range of about 7.8 toabout 8.2, and if necessary, aqueous (10%) hydrochloric acid NF can beadded to adjust the pH to 8.

The same procedure can be used to prepare a topical gel having 0.1%clonidine.

EXAMPLE 2

A pharmacokinetic study was conducted to compare absorption and otherpharmacokinetic characteristics following topical applications of dailydoses of 3 mg and 6 mg of clonidine employing a topical gel containing0.1 weight percent clonidine hydrochloride. The study mimicked therealistic use of topical clonidine gel by a patient with painfuldiabetic neuropathy of the feet and legs. For this study eight, however,normal (i.e., pain free) volunteer adults with no efficacy outcomes wereselected who met the following inclusion criteria.

Inclusion Criteria

1. 18 years of age or older.

2. Systolic blood pressure between 100 and 140 mm Hg; Diastolic bloodpressure between 60 and 90 mm Hg; Pulse greater than 50 beats perminuter (BPM).

3. Written informed consent provided at screening.

4. Abstention from caffeine on days of heavy blood sampling (last day ofeach treatment).

Excluded from the study were adults meeting the following exclusioncriteria.

Exclusion Criteria

1. Known allergy or hypersensitivity to clonidine.

2. Presence of altered skin integrity including but not limited to, skinwounds, skin abrasions or any disease state affecting dermal integrityor structure in designated application sites.

3. Known or suspected pregnancy.

4. Abnormal results from screening clinical laboratory testing(hematology, blood chemistry and urinalysis).

5. Administration of any medication by any route within one week ofstarting study (subjects taking oral contraceptives were allowed tocontinue this medication), or administration of topical productsincluding, but not limited to creams, ointments, lotions and gels to thedesignated application site was further restricted to within two daysbefore study entry.

6. History or presence of serious medical conditions.

7. Participation in another investigational drug study or use of anyclonidine containing product with the last month.

8. Smoking or illicit drug history.

9. Anemia of any etiology.

The study was designed as an unblinded randomized cross-over regimen inwhich two dose levels of clonidine (3 mg and 6 mg per day) were comparedto assess whether tissue saturation is dose related on the assumptiontopical clonidine forms a reservoir at non-specific binding sites withinthe skin. The regimen comprised the following six clinical studyperiods:

(1) Screening period. Initial vital signs (blood pressure, pulse,temperature) were taken in the morning.

(2) First Fourteen-Day Topical Clonidine Application Period (Study days1-14). On study Day 1 of topical clonidine gel application, vital signswere taken in the morning and blood samples were taken both in themorning and in the afternoon to determine clonidine plasma concentrationby Gas Chromatograph/Mass Spectrum analysis, having clonidinesensitivity of 0.025 ng/ml. On Days 2-13 of topical clonidine gelapplication, vital signs and blood samples were taken in the morningonly. On Day 14, only the morning dose of topical clonidine gel wasapplied and vital signs and blood samples were taken in the morning.Blood samples were also taken after 2, 4, 6, 8 and 12 hours followingthe application of this last dose.

(3) First Seven-day Blood Sampling Period (Study days 15-21). Vitalsigns and blood samples were taken in the morning.

(4) One week No-treatment Washout Period (Study days 22-28). Notreatment or clinical work performed.

(5) Second Fourteen-day Topical Clonidine Application With BloodSampling Period (Study days 29-42). The clinical procedure of studyperiod (2) was repeated.

(6) Second Seven-day Blood Sampling Period (Study days 43-49). Theclinical procedure of study period (3) was repeated.

Half of the randomized population started the treatment sequence with a3 mg/day dose during Study Period (2) and then followed with thecrossover sequence of the 6 mg/day dose during Study Period (5). Theother half of the population started the first treatment with the 6mg/day dose during Study Period (2) and then followed with the crossoversequence of the 3 mg/day dose during Study Period (5). The followingprotocol was employed for topical application of clonidine.

Clonidine dose of three mg/day. One dose of one mg clonidine gel wastopically applied to a selected area of the skin on the right lower legthree times a day for a total application of three mg clonidine/day tothe same designated skin area for a period of 14 consecutive days,during either Study Period (2) or Study Period (5).

Clonidine dose of six mg/day. A dose of one mg clonidine gel was appliedto a selected area of the right leg three times a day and one mgclonidine gel was applied to the same corresponding selected area on theleft leg three times a day for a total administration of 6 mgclonidine/day for 14 consecutive days, during either Study Period (2) orStudy Period (5).

The gel was applied and rubbed into the skin. The application site wasallowed to dry to the touch following application of the gel beforeclothing was allowed to contact the treated skin.

Individual tubes of topical gel containing 0.1 weight percent clonidinewere supplied for each volunteer. From these tubes, the daily total dosewas divided into three portions and applied three times dailyapproximately every eight hours. The clinical investigator's staffmeasured, dispensed and observed the application of the morning andafternoon doses and the volunteers measured and applied a bedtime dose.

The actual amount of gel applied for a total dose of 3 mg clonidine/daywas found to be a mean value of about 3.1 mg/day and for a total of 6 mgclonidine/day was found to be a mean value of about 6.2 mg/day.

The systemic plasma concentrations seen with topical applications of 3mg and 6 mg of clonidine per day are shown in FIG. 1. The datasummarized in FIG. 1 shows a maximum mean plasma concentration of about0.2 nanograms/ml at the 6 mg/day dose and about 0.05 nanograms/ml at the3 mg/day dose. These plasma concentrations are at the bottom or belowthe range considered as the antihypertensive therapeutic threshold of0.2 or 0.3 nanograms/ml. No side effects were observed in the eightvolunteers who applied the 0.1% formulation at doses of either 3 mg or 6mg per day for 14 consecutive days.

EXAMPLE 3

Several clinical trials were conducted to determine the bloodconcentration from topical administration as well as therapeuticeffectiveness in patients with sympathetically maintained peripheralneuropathic pain syndromes.

Patients suffering with sympathetically maintained neuropathic pain wereselected for two clinical trials, Study A and Study B, conducted todetermine the therapeutic effectiveness of a clonidine gel containing0.1 weight percent clonidine hydrochloride. In Study A, systemicclonidine blood concentration from topical administration was alsodetermined.

In Study A, nine patients were selected who were affected with bilaterallower extremity, painful diabetic neuropathy. In Study B, nine patientswere selected who were affected with postherpetic neuralgia on generallyirregular bodily areas of the trunk.

The ongoing neuropathic pain intensity was subjectively assessed on aNumeric Graphic Pain Score (NGPS) ranging from zero (0)=“No pain” to10=“Pain as bad as it could be.” Pain relief was also subjectivelyranked on a analog pain relief scale ranging from −1=More pain; zero(0)=No change; 1=Some relief; 2=Moderate relief; and 3=Complete relief.A baseline NGPS value was assessed before starting the trial, and bothNGPS and pain relief scores were assessed on each week of the trialfollowing topical application of the topical clonidine gel.

Each dose treatment was a period of seven days. The clonidine gel wasapplied by the patient to the affected painful region of the patient'sbody and rubbed into the skin. Sufficient topical gel was applied toprovide a predetermined unit dosage amount of clonidine and totalmilligram (mg) amount of clondine dose/day. The amount of clonidinedose/day was increased weekly by increasing the number of applicationsper day as described in the following protocol.

Study A. Week 1: Sufficient gel to provide a unit dosage amount of about0.625 mg clonidine per foot was applied twice a day for a total dailydose of 2.5 mg clonidine. Week 2: Sufficient gel to provide a unitdosage amount of about 0.625 mg clonidine per foot was applied threetimes a day, at spaced intervals of about 8 hours, to provide a totaldaily dose of 3.75 mg clonidine. Week 3: Sufficient gel to provide aunit dosage amount of about 0.625 mg clonidine per foot was applied fourtimes a day, at spaced intervals of about 6 hours, to provide a totaldaily dose of 5 mg clonidine.

For Study B, the protocol of Study A was repeated, except that each unitdosage amount applied was 0.5 mg clonidine for a total daily dose ofclonidine during week 1 of 1 mg; during week 2 of 1.5 mg; and duringweek 3 of 2 mg.

The individual and average NGPS and pain relief outcome data for Study Aand Study B, respectively, are shown in Tables 1 and 2 below.

TABLE 1 STUDY A Painful Diabetic Neuropathy Outcome Data (dosing in mgof clonidine/day) Clonidine 0.1% gel Baseline NGPS NGPS NGPS Pain ReliefPain Relief Pain Relief Patient # NGPS 2.5 mg 3.75 mg 5 mg 2.5 mg 3.75mg 5 mg 1 10 6 3 2 2 1 2 2 10 5 5 8 1 0 2 3 8 1 0 0 2 2 2 4 5 3 7 5 1 −11 5 10 5 8 5 0 0 0 6 8 5 4 4 1 1 1 7 8 6 5 0 2 1 2 8 7 8 7 DC 0 1 DC 9 46 1 1 1 2 2 Average 7.8 4.1 4.4 3.1 1.1 0.8 1.5 NGPS (Numeric GraphicPain Score) scores ranged from 0, “No Pain” to 10, “Pain as bad as itcould be” Pain Relief scores ranged from −1, More pain; 0, No change; 1Some relief; 2 Moderate relief; and 3 Complete relief DC = Discontinued

Eight of the nine patients with bilateral lower extremity, painfuldiabetic neuropathy, reported decreased pain scores or increased reliefscores. The systemic clonidine blood concentration was below the limitof detection (0.025 ng/ml) in all but two of 38 blood samples.

TABLE 2 STUDY B Postherpetic Neuralgia Outcome Data (dosing in mg ofclonidine/day) Clonidine 0.1% gel Baseline NGPS NGPS NGPS Pain ReliefPain Relief Pain Relief Patient # NGPS 1 mg 1.5 mg 2 mg 1.0 mg 1.5 mg 2mg 1 4 2 1 1 2 2 2 2 7 7 7 6 0 1 1 3 8 5 3 3 0 1 1 4 3 2 2 2 1 1 1 5 3 33 4 0 0 1 6 7 7 5 4 0 1 2 7 3 2 2 2 1 1 2 8 7 4 5 10 1 1 1 9 6 6 4 3 1 11 Average 5.3 4.2 3.5 3.9 0.7 1.0 1.3 NGPS (Numeric Graphic Pain Score)scores ranged from 0, “No Pain” to 10, “Pain as bad as it could be” PainRelief scores ranged from −1, More pain; 0, No change; 1 Some relief; 2Moderate relief; and 3 Complete relief

Seven of nine patients reported decreased pain scores. All patientsreported at least “some relief” at the 2 mg/day dose.

The data show that 15 of 18 patients (83%) were considered clonidineresponders. More significantly, the neuropathic pain these patientsexperienced was refractory to previous interventions.

EXAMPLE 4

The clinical trial procedure of Example 3 (Study A) was repeated, exceptthat ten patients were selected who were affected with bilateral lowerextremity, painful diabetic neuropathy and the treatment period wasincreased to two weeks. The six week trial (Study C) was conductedemploying the clonidine gel of Example 1 containing 0.05 weight percentclonidine hydrochloride. The patients applied sufficient topical gel tothe affected region to provide a predetermined unit dosage amount ofclonidine and the total mg amount of clonidine dose/day was increasedevery two weeks by changing the number of applications per day asdescribed in the following protocol.

Weeks 1 & 2: Sufficient gel to provide a unit dosage or about 0.31 mgclonidine per foot was applied twice a day to provide a total daily doseof 1.25 mg clonidine. Weeks 3 & 4: Sufficient gel to provide a unitdosage of about 0.31 mg clonidine per foot was applied three times a dayat spaced intervals of about eight hours to provide a total daily doseof 1.875 mg clonidine. Weeks 5 & 6: Sufficient gel to provide a unitdosage of about 0.31 mg clonidine per foot was applied four times a dayat spaced intervals of about six hours to provide a total dose of 2.5 mgclonidine.

The individual and average NGPS and pain relief outcome data are shownin Table 3 below.

TABLE 3 STUDY C Painful Diabetic Neuropathy Outcome (dosing in mg ofclonidine/day) Clonidine 0.05% gel Baseline NGPS NGPS NGPS Pain ReliefPain Relief Pain Relief Patient # NGPS 1.25 mg 1.875 mg 2.5 mg 1.25 mg1.875 mg 2.5 mg 1 5 5 3 3 1 2 2 2 6 4 2 4 1 2 2 3 6.5 7 6 6 2 2 2 4 5 53 2 1 2 2 5 4 3.5 2 1 2 2 2 6 6 5 5.5 4.5 1 1 2 7 4 1.5 1 2 2 2 2 8 8 55 0 2 2 3 9 8 7 7 0 2 2 3 10 3 1 3 0 2 2 3 Average 5.5 4.4 3.75 2.2 1.61.9 2.3 NGPS (Numeric Graphic Pain Score) scores ranged from 0, “NoPain” to 10, “Pain as bad as it could be” Pain Relief scores ranged from−1, More pain; 0, No change; 1 Some relief; 2 Moderate relief; and 3Complete relief

All ten patients with bilateral, lower extremity, painful diabeticneuropathy reported decreased pain scores and increased relief scores.

I claim:
 1. A topical aqueous gel in unit dose form, suitable fortransdermal administration of clonidine and consisting essentially of:clonidine in an amount in the range of about 0.05 to about 3.5milligrams per unit dose; water; and a water-gelling amount of apharmaceutically acceptable gelling agent; said clonidine being presentboth as clonidine free base and as clonidine hydrochloride, and at aconcentration in the range of about 0.01 to about 0.5 weight percent,and said aqueous gel having a pH value in the range of about 6 to about8.5.
 2. The topical aqueous gel in accordance with claim 1 wherein thepH value of the gel is about
 8. 3. The topical aqueous gel in accordancewith claim 1 further including a preservative.
 4. The topical aqueousgel in accordance with claim 3 wherein the preservative is benzylalcohol.
 5. The topical aqueous gel in accordance with claim 3 whereinthe preservative is a paraben compound.
 6. The topical aqueous gel inaccordance with claim 3 wherein the preservative is phenoxyethanol. 7.The topical aqueous gel in accordance with claim 1 wherein the gellingagent is a carbomer.
 8. The topical aqueous gel in accordance with claim7 further including glycerine polyacrylate as a minor portion of thegelling agent.
 9. The topical aqueous gel in accordance with claim 1wherein the gelling agent is glycerine polyacrylate. 10.The topicalaqueous gel in accordance with claim 1 further including askin-humectant adjuvant selected from the group consisting of polyhydricalcohols and polyglycerols.